Anemia was associated with elevated Alzheimer disease–related blood biomarkers and a higher risk of dementia among older adults, according to a cohort study published in JAMA Network Open.
Researchers analyzed data from 2,282 dementia-free adults aged 60 years or older in the Swedish National Study on Aging and Care in Kungsholmen. Over a mean follow-up of 9.3 years, 362 participants developed dementia.
Compared with those with normal hemoglobin levels, participants with anemia had a 66% higher hazard of developing dementia. Anemia was also associated with higher baseline levels of phosphorylated tau 217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP), which reflect Alzheimer disease pathology, neurodegeneration, and glial activation.
Among the biomarkers, the largest increases were observed for NfL and p-tau217, whereas GFAP elevations were more modest. Lower hemoglobin levels were associated with progressively higher dementia risk up to approximately 14 g/dL, after which the association plateaued.
Risk Highest With Anemia and Elevated Biomarkers
Dementia risk was highest when anemia co-occurred with elevated biomarker levels. Participants with both anemia and high NfL levels had a nearly fourfold higher hazard of developing dementia compared with those with neither factor. Similar patterns were observed for p-tau217 and GFAP, although the interaction was most pronounced for NfL.
The researchers suggested several possible explanations. Anemia may reduce brain resilience, lowering the threshold at which neuropathology manifests clinically as dementia. Alternatively, elevated NfL may reflect neurodegenerative processes that help mediate the association between anemia and dementia development.
Sex and APOE Findings
Associations between anemia, biomarker levels, and dementia risk were generally stronger in men than in women. Sex interactions were statistically significant for p-tau217 and NfL, but not GFAP. The researchers noted that women’s generally lower baseline hemoglobin levels may confer greater tolerance to anemia, potentially buffering its effects on brain health.
Effect modification by APOE epsilon 4 status was also observed. Anemia combined with low p-tau217 was associated with higher dementia risk among participants who were not APOE epsilon 4 carriers, but not among carriers. A statistically significant interaction with APOE epsilon 4 status was observed for NfL, but not GFAP.
Limitations and Interpretation
Several limitations should be considered. Hemoglobin and biomarker levels were measured only at baseline, limiting assessment of changes over time. A substantial number of participants were excluded because of missing data, and these individuals were generally older and had more comorbidities, which may have led to underestimation of associations. In addition, most anemia cases were normocytic, limiting evaluation of other anemia subtypes, and the cohort was predominantly White, which may affect generalizability.
As an observational study, the findings do not establish causation.
Still, the results suggest a potential biological interplay between anemia and neurodegenerative processes. “The highest dementia risk occurred when low hemoglobin and elevated AD biomarkers coexisted,” wrote lead study author Martina Valletta, MD, of Karolinska Institutet, and colleagues.
The researchers reported grant funding from Swedish research agencies and foundations; the funders had no role in the study design, analysis, or manuscript preparation. No other conflicts of interest were reported.
Source: JAMA Network Open
